Cefpodoxime proxetil, (R,S)-1-(isopropoxycarbonyloxy)ethyl-(+)-(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-((Z)-methoxyimino)acetamido]-3-methoxymethyl-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate, is a cephalosporin ester pro-drug which, when orally administered, converts to cefpodoxime, an antibacterial agent, through rapid hydrolysis by esterases present on the intestinal wall. Cefpodoxime exhibits a wide range of antibacterial activity against gram positive and negative bacteria, e.g., Staphylococcus aureus, Streptococcus aureus, E. coli, Klebsiella pneumonia and Proteuse vulgaris, and also a high degree of xcex2-lactamase stability.
The cefpodoxime proxetil of formula (I) is a xcex943-isomer prepared by various methods.
Hideo Nakao and Koich Huzimoto et al. reported a method of preparing cefpodoxime proxetil by reacting cefpodoxime with iodoalkylcarbonate in the presence of a base such as dicyclohexylamine (see J. of Antibiotics, vol. 40, pp. 370 (1987)). But the product obtained by this method is contaminated by about 3 weight % of the xcex942-isomers of formula (II) formed as a by-product. Due to the structure similarity, it is very difficult to separate the undesired by-product from the xcex943-isomer. The conversion of the xcex942-isomer to the xcex943-isomer has been attempted, but this process requires a series of reactions, and thus is not economically feasible. 
U.S. Pat. No. 5,498,787 discloses a method of preparing cefpodoxime proxetil from a cefpodoxime salt using a quaternary ammonium salt phase transfer catalyst, e.g., tetrabutylammonium hydrogensulfate in an amount ranging from 35 to 120 mole % based on cefpodoxime. The method can effectively inhibit the formation of the xcex942-isomer, but has problems in that the yield of the desired products is very low in the range of 50 to 60%, and the use of expensive quaternary ammonium salts is required.
In addition, according to the method disclosed in Korean Publication No. 99-54751, cefpodoxime proxetil is prepared by reacting a cephem compound of cefpodoxime with an alkylcarbonate to obtain an ester and then acylating the ester with an active ester form of arinothiazolyl acetic acid in the presence of a large amount of a quaternary ammonium salt. This method also requires the use of expensive quaternary ammonium salts and suffers from low productivity due to a long process time of about 3 days.
Accordingly, it is a primary object of the present invention to provide an improved process for preparing cefpodoxime proxetil of high purity.
In accordance with one aspect of the present invention, there is provided a method of preparing cefpodoxime proxetil of formula (I) which comprises reacting a cefpodoxime salt of formula (III) with 1-iodoethylisopropylcarbonate of formula (IV) in an organic solvent in the presence of a crown ether of formula (V): 
wherein, n is 1 or 2; M is an alkali metal or alkaline earth metal; and m is 4, 5 or 6.